Mycotoxins

The HBM4EU Scoping document on mycotoxins provides background information on these substances, identifies relevant policy questions on the group of substances and outlines research activities under HBM4EU.

The lead authors of the scoping document were Paula Alvito and Maria João Silva of National Institute of Health Dr. Ricardo Jorge (INSA) and Susana Viegas of Lisbon School of Health Technology(ESTeSL) The document was published in March 2019.

 This page was last updated in January 2020.

 

Uses of Mycotoxins

Mycotoxins are secondary fungal metabolites often found as natural contaminants in agricultural commodities all over the world and their occurrence pose a risk for human and animal health (Bennett and Klich, 2003; Wu et al., 2014). Generally, mycotoxins are chemically and thermally stable compounds, surviving storage and most production process (Koppen et al, 2010). Currently, the main human and animal health burdens of mycotoxin exposure are related to chronic toxicity, such as carcinogenic, teratogenic, immunotoxic, nephrotoxic, and endocrine disrupting effects. Chronic or even acute exposure to mycotoxins remains a daily fact, and therefore it is crucial that the mycotoxins’ metabolism is unravelled so more knowledge on biomarkers in humans and animals is required.

 

Hazardous properties of Mycotoxins

The major foodborne mycotoxins of public health concern are the aflatoxins (e.g. aflatoxin B1, AFB1), fumonisins (e.g. fumonisin B1, FB1), trichothecene mycotoxins (e.g. deoxynivalenol, DON), and ochratoxin A (OTA) (Wu et al, 2014). These are produced primarily by fungi of the genera Aspergillus, Fusarium, and Penicillium, which commonly infect food crops. The International Agency for Research on Cancer (IARC) classified some mycotoxins from carcinogenic to humans (e.g. aflatoxin B1, group 1) to not classifiable regarding its carcinogenicity to humans (e.g. deoxynivalenol, group 3) (IARC 1993, 2002, 2012). In the coming decades climate change is expected to impact fungal growth and agricultural practices (Battilani et al, 2016; Sundheim et al, 2017) and, consequently, mycotoxins’ concentrations and incidence in crops leading to an increase in human dietary exposure; (WHO, 2018; Assunção et al, 2018).

DON and FB1 were prioritized in the 2nd round of substance priorisation under HBM4EU and therefore, a more detailed review will be performed related to these mycotoxins.

Although there are structural alerts for DON as a suspected mutagen and carcinogen (Toolbox profiler Carcinogenicity by ISS) EFSA considers that DON is devoid of genotoxic potential (EFSA, 2014). Accordingly, IARC considers that there is inadequate evidence in experimental animals for its carcinogenicity (group 3, IARC, 1993).

Its hepatotoxicity has been shown (Peng et al., 2017) although has not been consensual and thereby a systematic discussion of the hepatic toxicity of DON is needed. DON is suspected to be toxic for reproduction and it is able to cross the human placenta (Nielsen et al., 2011). In addition, its teratogenic potential has been shown in animals (Yu et al., 2017) and deserves to be further studied. DON (and other trichothecenes), is immunotoxic, acting as a potent inhibitor of protein synthesis and stimulating the pro-inflammatory response (Sundheim et al., 2017). EFSA CONTAM Panel established a group TDI of 1 µg/kg bw per day for the sum of DON and itsacetylated and modified forms (3-Ac-DON, 15-Ac-DON and DON-3-glucoside) based on reduced body weight gain in mice.

In order to assess the acute human health risk, epidemiological data from mycotoxicoses were assessed and a group-ARfD of 8 µg/kg bw per eating occasion was calculated (EFSA, 2017).

FB1 is a suspected carcinogen according to the CLP classification and it is classified by IARC as possibly carcinogenic to humans (Group 2B, IARC, 2002). In vivo studies have shown that the repeated exposure to this toxin leads to liver and kidney toxicity (EFSA, 2018) and it is able to induce the formation of liver and kidney tumours (IARC, 2002). FB1 is not mutagenic in bacteria but it induces oxidative stress, being clastogenic to mammalian cells (EFSA, 2018). FB1 adverse effects are mainly mediated by the inhibition of ceramide synthases, which are key enzymes in sphingolipid metabolism. Based on the results of animal studies, JEFCA considered FB1 as a potential immunotoxic substance (WHO, 2011). It also causes developmental toxicity in several animal species (IARC, 2002). To derive HBGV for FB1, megalocytic hepatocytes in male mice were considered as the most appropriate outcome and a benchmark dose lower confidence limit 10% (BMDL10) of 165 µg/kg bw per day for FB1 was established (EFSA, 2018). The CONTAM Panel used the BMDL10 of 0.1 mg/kg bw per day and an uncertainty factor of 100 for intra and interspecies variability resulting in a TDI of 1.0 µg FB1/kg bw per day. Based on structural similarity and the limited data available indicating similar MoA and similar toxic potencies, the Panel decided that FB2, FB3 and FB4 should be included in a group TDI with FB1 (EFSA, 2018).

Recent surveys have highlighted the fact that humans are more frequently exposed to multiple than to single mycotoxins (Alvito et al, 2010; Solfrizzo et al., 2014; Alassane-Kpembi et al, 2016; Assunçao et al, 2016), raising a concern about their potential combined effect on human health. The presence of DON, FB1 and other mycotoxins was reported in foods (Sirot et al, 2013; De Boevre et al, 2013; Garcia-Moraleja et al, 2015; Assunção et al, 2016; Martins et al, 2018), in biological samples from general population (Heyndrickx, 2015; Vidal et al, 2016; Brera et al, 2015) and in occupational settings (Fromme et al, 2016; Viegas et al, 2018, 2018a). Besides the regulated mycotoxins, an increasing number of studies are paying attention to mixtures involving the “emerging” ones (beauvericin, enniantins, Alternaria toxins, etc.) (Alassane-Kpembi et al, 2017; Gruber-Dorninger et al, 2017; Puntscher et al, 2018). Other authors also refer the possible interactions between environment and food contaminants, cadmium and deoxynivalenol, in different target organs (Le TH et al, 2018).

 

Substances included in the Mycotoxins group

Please see the link to the scoping document on Mycotoxins at the top of the page for this information

 

Human exposure to Mycotoxins

Mycotoxins are commonly detected in cereal-based foods, cereals or fruit-based beverages, and several animal products (Bennett and Klich, 2003) and the general population is currently exposed by the oral route, via the ingestion of contaminated foods. Additional exposure routes include inhalation and dermal absorption, which can be particularly relevant for occupational exposure (Fromme et al, 2016; Viegas et al, 2015; Viegas et al, 2018).

Results of the BIOMIN Mycotoxin Survey conducted from January to March 2018 indicate that deoxynivalenol (DON) and fumonisins (FUM) are the most common mycotoxins found in food commodities and feedstuffs (https://www.biomin.net/en/biomin-mycotoxin-survey/ ).

DON is the most prevalent Fusarium toxin in European grains and its occurrence is frequently reported in cereals and cereal-based products such as bread, pasta, or beer (Marin et al., 2013), thereby main exposure is by oral route. A total of 72,011 results of DON and its metabolites in food were obtained from 27 reporting countries and were related to samples collected between 2007 and 2014 (EFSA, 2017).

According to EFSA (2017), the estimated chronic dietary exposure was above the TDI of 1 µg/kg bw/day for infants, toddlers and other children regarding the mean exposure scenario, and for adolescents and adults regarding the high exposure scenario, thus indicating a potential health concern. The EFSA CONTAM Panel noted that the overall human dietary exposure to the sum of DON and its metabolites, 3-Ac-DON, 15-Ac-DON and DON-3-glucoside was mainly driven by DON (EFSA, 2017). DON and DON-3-glucoside were absorbed, distributed, metabolized and rapidly excreted through urine as shown recently by a human intervention study after exposure to DON and DON-3-glucoside (Vidal et al, 2018b). The analysis of 24h urine samples revealed that DON-15-glucuronide was the most prominent urinary biomarker followed by free DON and DON-3-glucuronide. Other studies have reported the detection of DON (total DON) in the urine of the general population in UK (Turner et al, 2010a), France (Turner et al, 2010b), Sweden (Turner et al, 2010), Italy (Solfrizzo et al, 2014), Croatia (Sarkanj et al, 2013), Austria (Warth et al, 2012b), Belgium (Huybrechts et al, 2014) and Germany (Gerding et al, 2014).

Females and males show different patterns of exposure levels, and human exposure to DON also shows some geographical differences (Cheng et al, 2017; Vidal et al, 2018b). Additional exposure by inhalation in occupational settings were also reported (Fromme et al, 2016; Viegas et al, 2018).

The occurrence of FB1–3 is well documented in maize and products thereof and the main exposure route is the oral route (EFSA, 2018). Animal studies indicate that FB1 is poorly absorbed from the gastrointestinal tract and rapidly cleared from the blood by the biliary route, and preferentially excreted with the faeces (EFSA, 2018). In human biomonitoring studies FB1 has been detected in urine of the general population in Sweden (Wallin et al, 2012), Austria (Warth et al, 2012), Belgium (Ediage et al, 2012) and Germany (Gerding et al, 2014). Despite the low excretion rates for FB1 (0.93-2.6%) it has been proposed as biomarker of exposure. (Shephard et al. 1994; Dilkin et al. 2010; Gambacorta et al. 2013; Souto et al. 2017).

 

Technical challenges in biomonitoring Mycotoxins in humans

Mycotoxin exposure assessment throughout biomonitoring studies based on the analysis of mycotoxin themselves, protein or DNA adducts, and/or major phase I or phase II metabolites (e.g. glucuronide conjugates), in human biological samples such as urine, serum and breast milk, have provided useful information over recent years. Fast advances in LC–MS technology have allowed multiple mycotoxins to be analysed simultaneously (Ediage et al, 2012; Warth et al, 2013; Solfrizzo et al, 2014; EFSA, 2017; Sarkanj et al., 2018).

Recent progress in biomarker research has allowed the determination of DON and its metabolites in urine, primarily as DON-glucuronides, by using single or multiple biomarker methods. DON-15-glucuronide, the sum of DON-glucuronides, or total DON (sum of free DON + DON-glucuronides after deconjugation) are considered suitable DON-biomarkers of exposure in urine. DON-3-glucoside, a modified form of DON, has a similar excretion profile as DON with DON-15-glucuronide being the most abundant metabolite (Vidal et al, 2018b). To determine the urinary glucuronides, a preliminary approach was developed based on the enzymatic hydrolysis of deoxynivalenol-glucuronides, and subsequent determination of the “total DON” (sum of free and released mycotoxins by hydrolysis) (Solfrizzo et al, 2014; Turner et al, 2010). Afterwards, a direct method for quantification of glucuronides such as DON-3-glucuronide and DON-15-glucuronide was developed using in-house synthesized mycotoxin-standards (Ediage et al, 2012; Warth et al, 2013). These analytical developments permitted the scientific community to find strong correlations between the sum of urinary DON and its glucuronides (Vidal et al, 2018b). Most of the reported analytical methods for DON biomarker analysis in urine were sensitive enough to differentiate exposure levels. However, commercial sources for DON glucuronide standards are scarce and no certified reference materials are available for urinary DON biomarkers (EFSA, 2017). New trends in high-resolution MS for untargeted metabolic profiling and metabolomics may unravel and identify novel metabolites, biotransformation products and/or modified DON forms (EFSA, 2017; Vidal et al, 2018b; Sarkanj et al, 2018). Recently, DON-3-sulfate, a novel human metabolite and potential new biomarker of DON exposure was also reported in urine samples obtained from pregnant women in Croatia (Warth et al, 2016). Exposure to fumonisins can be assessed using urinary biomarkers. FB1–3 and hydrolysed form of FB1, HFB1, have been suggested as direct biomarkers of exposure by several authors (Shephard et al., 2007; Ediage et al, 2012; Heyndrickx et al., 2015). However, because of the poor urinary excretion of fumonisins and the consequent need for high sensitivity analytical procedures, the sample protocol requires an extensive clean-up and concentration step, based on SPE C18 cartridge or immunoaffinity purification. (EFSA, 2018).

 

Legislative status in the European Union

Following on the Advisory Board’s advice to strengthen the science-policy interface, HBM4EU developed a strategic and systematic approach to outreach and align science and policy. A legislative mapping exercise was done by RPA Consultants, providing relevant public policy processes that may benefit from the knowledge generated under HBM4EU. The documents are available for consultation here, with the tables presented here.

In Europe, the European Commission (EU) has introduced comprehensive mycotoxin regulations for food to facilitate world trade and protect consumer´s health (Cheli et al., 2014). The EU Regulation (EC) No 1881/2006 established the maximum permissible limits for aflatoxins (AFB1, sum of AFB1, AFB2, AFG1 and AFG2, AFM1), ochratoxin A (OTA), patulin (PAT), DON, zearalenone (ZEN), FBs (sum of FB1 and FB2), sum of T-2 and HT-2 toxins, and citrinine in specific food products (EC, 2006a and its amendments). This regulation also includes much lower regulatory limits for food for infants and young children due to their particular vulnerability and different consumption pattern. In addition to mycotoxin maximum levels, EU Regulation (EC) No 401/2006 provides sampling plans according to nine different groups of food commodities taking into account the heterogeneous distribution of mycotoxins in agricultural commodities (EC, 2006b).The issue of effects resulting from exposure to multiple toxins (combined effects) and from different routes (aggregated exposure) had particularly concerned policy makers because combined effects can differ from individual effects of each chemical contaminant (Bouaziz et al, 2008). Government and industry regulations are usually based on individual mycotoxin toxicities and do not take into account the complex dynamics associated with interactions between co-occurring groups of mycotoxins (Assunção et al., 2016; Kienzler et al., 2016).

Farmers need to continuously assess the risk from mycotoxins to both crops and animals. These good practices together with harmonized international legislation on permitted maximum levels will ensure that highly contaminated cereals do not enter the food chain. From growers to retailers, all food business operators following the rules set by Codex Alimentarius Committee are able to ensure that food is safe in every home (Codex Committee on Contaminants in Food).

Concerning inhalation, the absence of exposure limits makes it difficult to interpret the exposure values and to determine acceptable values for occupational settings, in order to ensure workers’ health (Viegas et al., 2018; Viegas et al., 2018a).

 

Policy questions on Mycotoxins

The following questions are mandatory for deoxynivalenol (DON) and its acetylated and modified forms and fumonisin B1 (FB1). Data on other mycotoxins could be added, if possible.

  1. Are there validated and harmonized analytical methods to assess the selected mycotoxin exposure biomarkers?
  2. What are the current exposure levels of the European population to the selected mycotoxins? Are there exposure data for other mycotoxins?
  3. Does the exposure to mycotoxins differ among countries/EU geographical regions and different population groups? Which are the main factors related with these differences (age, gender, occupational settings, geographic localisation, season/year)?
  4. Is there a time trend in human exposure to mycotoxins across Europe? Which are the identifiable factors associated with these trends (regulation related with food safety, climate change, others)?
  5. Are there exposure models and toxicokinetics data for mycotoxins? Which are their limitations?
  6. Is the risk associated with human exposure to these mycotoxins characterized? Are there health impact assessment studies? Is it possible to set a HBGV for mycotoxins in biological samples?
  7. Does the aggregate exposure to mycotoxins/other food contaminants contribute to combined effects? What are the knowledge gaps for risk assessment?
  8. Which are the key-events that determine the long-term health effects from low-dose continuous exposure to the target mycotoxins? Which are the health effects associated with high short-term exposure by inhalation (occupational exposure)?
  9. Which are the most reliable and meaningful effect biomarkers for single and combined effects?
  10. Are there mycotoxins (including metabolites masked and/or other modified forms) besides those covered by the current risk assessment, which could be potentially relevant concerning their (co-) occurrence and toxicological properties?

Please find answers to the updated (2020) Policy-related questions on Mycotoxins here 

 

Stakeholder comments on the scoping document

In the interest of transparency and accountability, HBM4EU invites interested stakeholders to submit comments on the scoping document on acrylamide.

All submitted comments will be made available for download on this webpage and will be taken into consideration by the HBM4EU consortium, where possible.

Please click here to submit your comments.

 

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